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Hyperinflammatory and Hypoinflammatory phenotypes have been identified in observational cohorts and clinical trials of acute respiratory distress syndrome (ARDS). In the Reevaluation of Systemic Early Neuromuscular Blockade (ROSE) trial of cisatracurium for moderate to severe ARDS, we addressed three unanswered questions: 1) Do the same phenotypes emerge in more severe ARDS patients recruited earlier in the hospital course? 2) Do phenotypes respond differently to neuromuscular blockade? and 3) What biological pathways most differentiate molecular phenotypes? We performed latent class analysis in ROSE using pre-randomisation clinical and protein biomarkers. We then sequenced whole blood RNA from enrollment (Day 0) and Day 2 samples in 134 patients (N= 67 for each phenotype). At each time point, independently, we performed differential gene expression (DGEA) and …